Dopamine is a highly significant neurotransmitter in the central nervous system, playing a central role in cognition, motor control, and the regulation of emotion. Dysfunction in central dopamine systems is implicated in a number of disorders, including Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, and substance abuse. Pathological alterations in the extracellular concentration of dopamine in the brain are generally viewed as the hallmark of dopaminergic dysfunction, which makes the quantitative determination of extracellular dopamine concentrations in the living brain a highly significant objective. However, the penetration of living brain tissue with dopamine-sensitive probes has traumatic consequences that can alter the state of brain dopamine systems and inhibit quantitative dopamine determination. One strategy for diminishing the trauma associated with in vivo measurements is to decrease the size of the probes by adopting amperometric and voltammetric microelectrode technologies. This proposal will investigate whether the diminished trauma associated with microelectrodes enables fundamentally new understanding of brain dopamine systems. Aim 1 will examine extracellular dopamine concentrations in transgenic mice lacking the dopamine transporter to test the hypothesis that previous indications that these hyperactive animals exhibit elevated extracellular dopamine levels were confounded by the uncertainty associated with brain trauma. Aim 2 will test the hypothesis that dopamine:glutamate interactions in the rat striatum involve the diffusion of neurotransmitters between closely apposed dopamine and glutamate terminals located within micrometer distances of implanted voltammetric and amperometric microelectrodes. Aim 3 will evaluate stress and glial activation associated with voltammetric microelectrodes. And, Aim 4 will evaluate disruption of the vascular bed surrounding microelectrode implantation sites as a potential mechanism underlying penetration trauma. Collectively, these studies will establish the extent, time course, and nature of penetration injury associated with in vivo dopamine measurements and show that diminished measurement-injury enables fundamentally new understanding of the role of dopamine systems in normal brain function and the dysfunction associated with brain disorders.